Title

Designing The Polyamine Pharmacophore: Influence Of N-Substituents On The Transport Behavior Of Polyamine Conjugates

Abstract

N-Ethylated N-arylmethyl polyamine conjugates were synthesized and evaluated for their ability to target the polyamine transporter (PAT). To understand the effect of N-ethylation upon PAT selectivity, ethyl groups were appended onto a PAT-selective N1-anthracenenylmethyl homospermidine derivative. 1b. Bioevaluation in L1210 murine leukemia cells and in two Chinese hamster ovary cell lines (PAT-active CHO and PAT-deficient CHO-MG) revealed a dramatic decrease in PAT targeting ability upon N1 or N5 ethylation of the pharmacophore 1b. Experiments using the amine oxidase inhibitor, aminoguanidine (AG, 2 mM), revealed that the N9-ethyl and N9-methyl analogues were able to retain their PAT selectivity and cytotoxicity properties in the presence or absence of AG. In contrast, the lead compound 1b (containing a terminal NH2 group) revealed a dramatic reduction in both its PAT-targeting ability and cytotoxicity in the absence of AG. An improved balance between these three properties of PAT-targeting, cytotoxicity and metabolic stability can be attained via N-methylation at the N9-position. © 2008 American Chemical Society.

Publication Date

4-24-2008

Publication Title

Journal of Medicinal Chemistry

Volume

51

Issue

8

Number of Pages

2551-2560

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1021/jm701341k

Socpus ID

43049137323 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/43049137323

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